Does Inflammation Trigger Insulin Resistance and Diabetes?

Nearly 21 million Americans suffer from type 2 diabetes, and every year 800,000 more are diagnosed. Considering the growing numbers, scientists are trying to fit together the disease’s disparate puzzle pieces. People who acquire it are typically obese, suffer from chronic inflammation and are resistant to insulin, the hormone that removes sugar from the blood and stores it as energy. For years no one has known exactly how the three characteristics are related, if at all. But a handful of recent studies suggest that they are inextricably linked through the actions of specific inflammatory immune cells and a master genetic switch—and the hope is that an understanding of the relations could open the door to new therapeutic opportunities.

Several decades ago scientists noticed that people with type 2 diabetes have overly active immune responses, leaving their bodies rife with inflammatory chemicals. In the early 1990s researchers at Harvard University pinpointed one major immune player as TNF-alpha, a chemical secreted by immune cells; such compounds are generally referred to as cytokines. They found high levels of the cytokine in the fat tissue of rats with type 2 diabetes, and when they bred obese rats that could not make the cytokine, diabetes did not develop in the animals. Researchers have since shown that TNF-alpha—and, more generally, inflammation—activates and increases the expression of several proteins that suppress insulin-signaling pathways, making the human body less responsive to insulin and increasing the risk for insulin resistance.

So what causes the inflammation? Although type 2 diabetes can develop in patients of normal weight, most scientists agree that “obesity is the driving force,” says Jerrold Olefsky, an endocrinologist at the University of California, San Diego. After fat cells have expanded as a result of weight gain, they sometimes do not get enough oxygen from the blood and start to die, he explains. The cellular death recruits immune cells to the scene.

Insulin resistance causes inflammation, too. In a study published in the August online version of Diabetes, H. Henry Dong and his colleagues at the University of Pittsburgh showed that a protein called FOXO1 serves as a master switch that turns on the expression of another key inflammatory cytokine, interleukin 1-beta, which also interferes with insulin signaling. Normally insulin keeps FOXO1 in check; it “rapidly inhibits FOXO1” by moving it out of the nucleus so it can be targeted for degradation, Dong says. But when a person becomes insulin-resistant and pancreatic cells no longer produce enough insulin to overcome the resistance, activity of FOXO1 increases.

Dong’s results suggest that inflammation and insulin resistance reinforce each other via a positive feedback loop. And indeed, the two often come together: for instance, rheumatoid arthritis, an inflammatory disease, heightens the risk of insulin resistance developing, Dong states.

The findings could lead to the development of new therapeutics. Dong says that “we are trying to create an antagonist, a molecule, to inhibit FOXO1 activity” enough to end diabetes but not so much as to impair FOXO1’s other roles in the body, which include aiding muscle cell growth.

Other scientists are targeting the immune cells that release cytokines. In 2003 researchers at Columbia University and at Millennium Pharmaceuticals discovered hoards of macrophages, immune cells whose primary role is to engulf pathogens, in the fat stores of people with type 2 diabetes. Olefsky and his colleagues later genetically engineered mice that could not produce these macrophages and showed that “the animals were protected from obesity-induced insulin resistance,” even if they were fat, he says. “That throws out the idea that if you could find a less noxious way in humans of inhibiting that macrophage inflammatory program, you could have a therapeutic.” The key would be to ensure that such a drug did not interfere with essential immune system activity, Olefsky notes.